Nerve growth factor (NGF) is synthesized and secreted by rat C6 glioma, a nervous system- derived cell line. The NGF content of these cells is increased by beta-adrenergic agonists, which cause an elevation of cyclic AMP content and the concomitant activation of cAMP-dependent protein kinase. The increase of NGF content does not depend on the increase in protein synthesis which is elicited by isoproterenol, whereas the increase of cyclic nucleotide phosphodiesterase (PDE) does. There are two forms of PDE in the cells; the cyclic AMP-specific form is induced by beta-adrenergic agonists, whereas the second form hydrolyzes cAMP or cGMP and is regulated by calcium and calmodulin. The induction of PDE requires translocation of the catalytic subunit of cytosol protein kinase into the nucleus, a process which is inhibited by treatment of the cells with vinblastine or colchicine. Phosphorylation of acidic nuclear proteins is also required for PDE induction; this phosphorylation can be blocked by cordycepin. RNA polymerase II is required for synthesis of PDE mRNA and treatment of the cells with either actinomycin or alpha-amanitin inhibits RNA polymerase and blocks PDE induction.